Ion Channels Offer Possible Biotech/Neurotech Synergy

by Warren Grill, senior technical editor, and James Cavuoto, editor

Since the beginning of the neurotechnology industry, the field has defined itself with electronic devices to stimulate or record from neural tissue. The biotech industry, by contrast, has defined itself with chemical and genetic engineering methods of modulating the behavior of cells, tissues, and organs. A common technique is to identify chemical receptors on specific targeted cells that respond to specific genetically engineered compounds.

While these two approaches have generally been distinct and independent endeavors, there is at least one area of overlap between neurotech and biotech applications, and that involves ion channel kinetics. Ion channels are gates in the membrane of neural cells that regulate the concentration of charged elements such as potassium, calcium, or sodium inside and outside the cell membrane.

Thus, biological or pharmacological techniques that affect the kinetics of ion transport across a neural membrane become, in essence, a form of electrical stimulation in that they produce electrical activation—or deactivation—of neurons just as if a stimulating electrode had produced the change in ion channel kinetics. Indeed, this area of overlap represents perhaps one of the most promising synergies between traditionally device-oriented neurotechnology and traditionally molecular-oriented biotechnology.

The value of ion-channel kinetics to neurotechnology applications is the potential to deliver stimulation only to specific classes of neural cells, instead of broadly to all cells in the vicinity of the stimulating electrodes. Conversely, the value of neurotechnology to biotech firms and researchers pursuing ion-channel approaches is the availability of electronic models that help monitor, diagnose, and predict the resulting behavior of neural cells and brain subsystems.

For example, one important aspect of neurotechnology is the use of electrical stimulation to activate the nervous system. Although electrical methods have been developed to block transmission of activity in nerve fibers, electrical techniques to reversibly silence neurons are lacking. Two different research teams have recently published reports in the Journal of Neuroscience that present genetic engineering methods of reversibly silencing selected neurons.
Lechner and colleagues from The Salk Institute, in La Jolla, CA used exogenously expressed allostatin receptors and G-protein coupled potassium channels to modulate the excitability of cultured cortical neurons. Following application of allostatin, the receptors were activated and, through a G-protein mediated second messenger cascade, activated the potassium channels. The activated potassium channels hyperpolarized the cell membrane and decreased neuronal excitability by a factor of 10.

The decrease in excitability occurred within minutes of the application of allostatin, and similarly was reversed within minutes of allostatin removal. These results thus demonstrate a novel genetic technique to quickly and reversibly reduce the excitability of neurons. Further, as the allostatin receptor is not normally present in mammalian neurons, its selective expression could be used to limit effects to targeted groups of neurons.

A similar approach was reported by Slimko and colleagues from California Institute of Technology. They expressed ivermectin-sensitive chloride channels in cultured hippocampal neurons. Following application of ivermectin, the chloride channels opened, decreasing the membrane resistance and allowing chloride ions to flow into the cells. The influx of chloride hyperpolarized the cell membrane and, in combination with the decrease in membrane resistance, reduced excitability of the cells.

The time course of the influx of chloride and decrease in membrane resistance was dependent on the concentration of ivermectin applied. At high concentration the chloride conductance was activated in less than one second following application of ivermectin, but at a 100-fold lower concentration the conductance took hundreds of seconds to activate completely. The time to reverse the ivermectin-activated conductance, however, was between one and eight hours.

These novel biotech tools enable the modulation of the excitability of selected populations of neurons. Such methods will prove exceptionally important in determining the role of specific neurons in regulation of behavior, and could be a harbinger of future treatments where aberrantly firing neurons are switched off with genetic techniques.

There are currently several commercial biotech firms working on ion-channel approaches to nervous system modulation. Neurobiological Technologies Inc. of Richmond, CA is a drug discovery firm concentrating on neuroprotective and neuromodulatory agents. The firm has developed potential drugs that control the flow of calcium ions across the neural membrane in certain forms of neuropathology.

Another firm, NeurogesX, Inc. of San Carlos, CA, has identified specific receptors in pain fibers that can be blocked, using a chemical agent called capsaicin, without blocking other sensory and motor fibers. Synaptic Pharmaceutical Corp. of Paramus, NJ, has used its expertise in G-protein-coupled receptors to identify receptors in specific neural cells that can be blocked for potential treatment of disorders such as incontinence and depression.

As products such as these reach later stages of commercial development, and as neurostimulation devices become more compact, localizable, and integrated with the extracellular matrix within the nervous system, the opportunities for interaction between biotech and neurotech device approaches to the nervous system will expand considerably. Presumably, the opportunities for business and commercial synergy will expand as well.